Ferrocenyldiphospine-ruthenium complexes and a hydrogenation process of exocyclic double bond of d-thiophene to d-thiophane

ABSTRACT

Ferrocenyldiphosphin-ruthenium complexes are new and good catalysts for the hydrogenation of exocycilc double bond of d-Thiophene 3 to d-Thiophane 4, both of which are intermediates of D-Biotin 1 synthesis.  
                 
 
     in which R signifies —OCH 3 (3a), —OCH 2 CH 3 (3b), —CH 2 COOH(3c), —CH 2 COOCH 3 (3d) or —CH 2 COOEt(3e) and Bz signifies benzyl group

FIELD OF THE INVENTION

[0001] The present invention relates to new homogeneousferrocenyldiphosphine-ruthenium complexes, good catalysts for thehydrogenation of d-thiophene to d-thiophane, and to a new process forthe hydrogenation of d-thiophene 3 to d-thiophane 4 usingferrocenyldiphosphine-ruthenium complexes as catalysts.

BACKGROUND OF THE INVENTION

[0002] D-Biotin is one of the water-soluble B vitamins. It plays anessential role as a coenzyme in carboxylation reactions related tobiochemical processes such as gluconeogenesis and fatty acidbiosynthesis.

[0003] D-Biotin deficiency in poultry and swine causes a series ofsevere symptoms. These deficiencies are corrected by feeding Biotin as afeed additive. Hence, it is commercial importance.

[0004] Goldberg and Stembach's synthetic scheme, improved later byGerecke etal, is regarded to be still one of the most efficientprocesses for the commercial production of natural-form D-Biotin. [U.S.Pat. No. 2,489,232, U.S. Pat. No. 2,489,235; U.S. Pat. No. 2,489,238;Helv. Chim. Acta, vol.53, 991(1970)].

[0005] The present invention relates to new homogeneousferrocenyldiphosphine-ruthenium complexes, good catalysts for thehydrogenation of d-thiophene to d-thiophane, and to a new process forthe hydrogenation of d-thiophene of the formula 3 to d-thiophane of theformula 4 using ferrocenyldiphosphine-ruthenium complexes as catalysts.

[0006] in which R signifies —OCH3(3a), —OCH₂CH₃(3b), —CH₂COOH(3c),—CH₂COOCH₃(3d) or —CH₂COOEt(3e) and Bz signifies benzyl group

[0007] d-Thiophene of the formular 3, which is derived from the reactionof d-Thiolactone of the formula 2 with appropriate Grignard or Wittigreagents, is the intermediate of D-Biotin synthesis.

[0008] Up to the present time, the conversion of d-Thiophene of theformula 3 to d-Thiophane of the formula 4 with the desired all-cisconfiguration at centers C-2, C-3, and C-4(see atom numbering onD-Biotin structure of the formula 1) is known to be accomplished by thecatalytic hydrogenation using Palladium on carbon, Palladium hydroxideon carbon or Nickel catalyst, the heterogeneous catalysts.

[0009] However, many disadvantage are experienced with the uses of theheterogeneous catalysts. Palladium on carbon (dry form) is veryexpensive, air-sensitive and susceptible to sulfur poison. Palladiumhydroxide on carbon is also expensive and sensitive to air. Nickelcatalyst is less expensive but requires high pressure and hightemperature for the hydrogenation of exocyclic double bond, which maynot be adequate for the commercial applications.

SUMMARY OF THE INVENTION

[0010] We found out new homogeneous catalysts for the hydrogenation ofexocyclic double bond transforming d-thiophene of the formular 3 tod-thiophane of the formula 4, exhibiting the desired all-cisconfiguration at C-2, C-3 and C-4 centers. The homogeneous catalysts, wewant to report herein, are new Ferrocenyldiphosphine-ruthenium complexessuch as 1,1′-Bis(diphenylphosphino)-ferrocene-ruthenium complex, whichcompensate all disadvantages inheriting from the uses of knownheterogeneous catalysts.

[0011] The above-mentioned new homogeneous catalysts which we inventedare less expensive, less sensitive to air, easy to handle. lesssusceptible to sulfur poison, and do not require high pressure and hightemperature.

DETAILED DESCRIPTION OF THE INVENTION

[0012] Accordingly, the object of the present invention is to prividenew homogeneous ferrocenyldiphosphine-ruthenium complexes whichcompensate all disadvantages of the known heterogemeous catalysts andwhich can replace existing heterogeneous catalysts such as Palladium andNickel catalysts for the hydrogenation of exocyclic double bond of thed-thiophene of the formula 3.

[0013] in which R signifies —OCH₃(3a), —OCH₂CH₃(3b), —CH₂COOH(3c),—CH₂COOCH₃(3d) or —CH₂COOEt(3e) and Bz signifies benzyl group

[0014] Other object of the present invention is to provide a new methodwhich utilizes the homogeneous catalysts for the hydrogenation ofexocyclic double bond transforming d-thiophene of the formula 3 tod-thiophane of the formula 4, exhibiting the desired all-cisconfiguration at C-2, C-3 and C-4 centers.

[0015] The object of the present invention is achieved by prividing aFerrocenyldiphosphine-ruthenium complex selected from the groupconsisting of the complexes whose formulas are described as follow:

[0016] 1. RuCl₂(COD)_(n)+PP in situ,

[0017] 2. [RuCl₂(PP)]₂(NEt₃), and

[0018] 3. RuHCl(PP)₂

[0019] wherein

[0020] COD signifies cyclooctadiene of the following formula,

[0021] and PP signifies a diphosphine ligand of the general formula

[0022] in which R is C₁-C₁₂ alkyl, C₅-C₁₂ cycloalkyl, C₁-C₄ alkyl orC₁-C₄ alkoxy-substituted, C₅-C₁₂ cycloalkyl, phenyl or phenyl which issubstituted by 1 to 3 identical or different members selected from thegroup consisting of C₁-C₄, alkyl, C₁-C₄ alkoxy or halogen.

[0023] n is an integral number of 1-3 and the complexes of n=1, n=2 orn=3 exist together with one another.

[0024] In an economical view point, the most efficient catalyst, amongall tested complexes, is{[1,1′-Bis(diphenylphosphino)ferrocene]dichlororuthenium(II){₂(triethylamine)[RuCl₂(BPPF)]₂(NEt₃)]complex whose ligand is known and can be prepared as described in J. J.Bishop etal, J. Organometal Chem. 1971, 27, 241.

[0025] Examples of suitable solvents of the reaction are aromatichydrocarbons such as benzene or toluene, ethers such as diethyl ether,tetrahydrofuran or dioxane, chlorinated hydrocarbons such asdichloromethane or dichloroethane, alcohols such as methanol, ethanol orisopropyl alcohol, esters such as ethyl acetate or butyl acetate andmixtures of these solvents with one another. Preference is given tousing methanol.

[0026] The addition of small amount of toluene to the substrateincreases the hydrogenation rate, of which the amounts range from 1% to50%, preferably 10%. However, the presence of water exhibits theopposite effect. The content of up to 0.1% water does not deterioratethe hydrogenation rate.

[0027] The hydrogenation is carried out at a temperature of from 20° C.to 150° C., preferably at 20° C. to 100° C., and at a pressure of from 1kg/cm² to 200 kg/cm², preferably 10 to 30 kg/cm². The reaction time is 5hours to 3 days, preferably 12-24 hours.

[0028] The comparative results of the hydrogenation of d-Thiophene 3 tod-Thiophane 4, with various Ferrocenyldiphophine-ruthenium complexes areshown in Table 1.

[0029] The Ferrocenyldiphosphine-ruthenium complex prepared in situgives only the yield of 50%, however, the isolated complex,[RuCl₂(BPPF)₂(NEt₃)], (Entry 1) improves the yield to 85.1%. When thereaction conditions are optimized further, the yields are increased evenhigher, as shown in Table 2.

[0030] Analyses of the yield of 4a in the catalytic hydrogenation areconducted with the following instrument.

[0031] High-Performance Liquid Chromatography: SHIMADZU SCL-10A

[0032] Column: KROMASLI C₈

[0033] Solvent: Acetonitrile/Water(1:1 by volume) at a flow rate 1.5ml/min.

EXAMPLE 1 Preparation of RuHCl(BPPF)₂

[0034] 2 g(7 mmol) of [RuCl₂(COD)]n (n=1-3), 8 g(14 mmol) of[1,1′-Bis(diphenylphosphino)ferrocene], 4.4 ml of triethylamine and 200ml ethanol were introduced into a reactor and refluxed with heating for6 hours under nitrogen atmosphere. After completion of the reaction,ethanol was distilled away, the residue was dissolved by adding 20 ml ofdichlormethane and the insoluble portion was removed by filtration.Ether was gradually added to the filltrate to recrystallize The crystalsprecicptated were filtered by filtration and dried in vacuo to obtainyellow solid.

EXAMPLE 2 Preparation of [RuCl₂(BPPF)]₂(NEt₃)

[0035] In a 250 ml Schlenk's tube were placed 2 g(7 mmol) of[RuCl₂(COD)]_(n) (n=1-3) and 4 g(7 mmol) of BPPF. After sufficientlyreplacing the inside atmosphere of the tube with nitrogen, 4.2 ml oftriethylamine and 40 ml of toluene were added thereto, and the resultantmixture was heated under reflux for 10 hours to perform reaction. Aftercooling the reaction mixture, the solid precipitated were separated byfiltration and dried in vacuo obtain orange solid.

EXAMPLE 3 Production of d-Thiophane, 4a

[0036] In a 100 ml stainless steel autoclave, the inside atmosphere ofwhich had previously been replaced with argon, were placed 13 g(33 mmol)of d-Thiophene, 3a, 25 ml of methanol, 1.25 ml of toulene and then,0.0092 g(0.0034 mmol) of[RuCl₂(COD)]n (n=1-3) and 0.0183 g (0.0034 mmol)of BPPF was added in situ to the mixture to perform hydrogenation for 24hours at a hydrogen pressure of 34 kg/cm² and at a reaction temperationof 100° C. Thereafter, the solvent was distilled off to obtain 6.53 g ofd-Thiophane, 4a, The yield thereof was 50%.

EXAMPLE 4 Production of d-Thiophane, 4a

[0037] In a 100 ml stainless steel autoclave, the inside atmosphere ofwhich had previously been replaced with argon, were placed 13 g(33 mmol)of d-Thiophene 3a, 25 ml of methanol, 1.25 ml of toluene and then, 0.041g(0.0034 mmol) of RuHCl(BPPF)₂ prepared in Referential Example 1 wasadded to the mixture to perform hydrogen for 24 hours at a hydrogenpressure of 34 kg/cm² and at a reaction temperature of 100° C.Thereafter, the solvent was distilled off to provide 7.45 g ofd-Thiophane, 4a. The yield thereof was 57%.

EXAMPLE 5 Production of d-Thiophane, 4a

[0038] In a 100 ml stainless steel autoclave, the inside atmosphere ofwhich had previously been replaced with argon, were placed 13 g(33 mmol)of d-Thiophene, 3a 25 ml of methanol, 1.25 ml of toluene and then, 0.062g (0.039 mmol) of [RuCl₂(BPPF)]₂(NEt₃) prepared in Referential Example 2was added to the mixture to perform hydrogenation for 24 hours at ahydrogen pressure of 34 kg/cm² and at a reaction temperature of 100° C.Thereafter, the solvent was distilled off to provide 13.02 g ofd-Thiophane, 4a, The yield thereof was 99.7%. TABLE 1 CatalyticHydrogenation of 3a with various Ru Complexes.^(a) Entry Catalyst S/Cratio Yield (%) 1 [RuCl₂(COD)]n + BPPF in situ 1000 50.0 2 RuHCl(BPPF)₂1000 57.0 3 [RuCl₂(BPPE)]₂(NEt₃) 1000 85.1

[0039] TABLE 2 Catalytic Hydrogenation of 3a with[RuCl₂(BPPF)]₂(NEt₃).^(a) Entry Reaction Time (h) T (° C.) Toluene(%)^(d) Yield (%) 1 24  60 0 78.4 2 24 120 0 67.8 3 24 100 0 85.1 4 48100 0 85.4 5 72 100 0 88.4^(b) 6 24 100 5.0 86.6 7 24 100 8.0 91.8 8 24100 12.0 92.8 9 24 100 12.0 99.7^(c) 10  24 100 25.0 45.4

[0040] Up to the present time, the conversion of d-Thiophene tod-Thiophane is known to be accomplished by the catalytic hydrogenationusing the heterogeneous catalysts such as Palladium on carbon, Palladiumhydroxide on carbon or Nickel catalyst.

[0041] However, many disadvantage are experienced with the uses of theheterogeneous catalysts. These heterogeneous catalysts are veryexpensive, air-sensitive, susceptible to sulfur poison and require highpressure and high temperature.

[0042] As the present invention, catalytic hydrogenation is accomplishedby using new homogeneous ferrocenyldiphosphine-ruthenium complexes whichcompensate all disadvantages inheriting from the uses of theabove-mentioned heterogeneous catalysts.

1. A homogeneous Ferrocenyldiphosphine- ruthenium complex selected fromthe group consisting of the complexes whose formulas are described asfollow:
 1. RuCl₂(COD)_(n)+PP in situ,
 2. [RuCl₂(PP)]₂(NEt₃) and 3.RuHCl(PP)₂ wherein COD signifies cyclooctadiene of the followingformula,

and PP signifies a diphosphine ligand of the general formula

in which R is C₁-C₁₂ alkyl, C₅-C₁₂ cycloalkyl, C₁-C₄ alkyl or C₁-C₄alkoxy-substituted, C₅-C₁₂ cycloalkyl, phenyl or phenyl which issubstituted by identical or different members selected from the groupconsisting of C₁-C₄, alkyl, C₁-C₄ alkoxy or halogen. n is an integralnumber of 1-3 and the complexes of n=1, n=2 or n=3 exist together withone another.
 2. A process for the hydrogenation of exocyclic double bondd-thiophene of the formula 3 to d-thiophane of the formula 4,

in which R signifies —OCH₃(3a), —OCH₂CH₃(3b), —CH₂COOH(3c),—CH₂COOCH₃(3d) or —CH₂COOEt(3e) and BZ signifies benzyl group. by usinga homogeneous Ferrocenyldiphosphine- ruthenium complex catalyst selectedfrom the group consisting of the complexes whose formulas are describedas follow:
 1. RuCl₂(COD)_(n)+PP in situ,
 2. Ru₂Cl₄(PP)₂(NEt₃) and 3.RuHCl(PP)₂ wherein COD signifies cyclooctadiene of the followingformula,

and PP signifies a diphosphine ligand of the general formula

in which R is C₁-C₁₂ alkyl, C₅-C₁₂ cycloalkyl, C₁-C₄ alkyl or C₁-C₄alkoxy-substituted, C₅-C₁₂ cycloalkyl, phenyl or phenyl which issubstituted by identical or different members selected from the groupconsisting of C₁-C₄, alkyl, C₁-C₄ alkoxy or halogen. n is an integralnumber of 1-3 and the complexes of n=1, n=2 or n=3 exist together withone another.
 3. The process of claim 2 wherein the hydrogenationreaction is carried out in an organic solvent selected from the groupconsisting of aromatic hydrocarbon(e.g. benzen or toluene), straightether(e.g.dimethyl ether or diethyl ether), cyclic ether(e.g.tetrahydrofuran or dioxane), chlorinated hydrocarbon(e.g.dichloromethane or dichloroethane), alcohol(e.g. methanol, ethanol orisopropyl alcohol), ester(e.g. ethyl acetate or butyl acetate) ormixture thereof.
 4. The process of claim 2 or 3 wherein thehydrogenation reaction is carried out in a mixed solvent of an aromatichydrocarbon(e.g. benzene or toluene) with an other organic solventselected from the group consisting of straight ether(e.g.dimethyl etheror diethyl ether), cyclic ether(e.g. tetrahydrofuran or dioxane),chlorinated hydrocarbon(e.g. dichloromethane or dichloroethane),alcohol(e.g. methanol, ethanol or isopropyl alcohol), ester(e.g. ethylacetate or butyl acetate).
 5. The process of claim 2, 3 or 4 wherein thehydrogenation reaction is carried out in the mixed solvent of tolueneand methanol.